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G. D. Pennock, P. H. Spooner, C. E. Summers and S. E. Litwin. Prevention of Abnormal Sarcoplasmic Reticulum Calcium Transport and Protein Expression in Post-infarction Heart Failure Using 3,5-Diiodothyropropionic Acid (DITPA).Journal of Molecular and Cellular Cardiology(2000) 32, 1939–1953. Heart failure of diverse causes is associated with abnormalities of sarcoplasmic reticulum (SR) Ca2+transport. The purpose of this study was to determine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA), prevents abnormal Ca2+transport and expression of SR proteins associated with post-infarction heart failure. New Zealand White rabbits were randomly assigned to circumflex artery ligation or sham operation, and to DITPA administration (3.75 mg/kg/day) or no treatment in a two-by-two factorial design. After 3 weeks, echo-Doppler and LV hemodynamic measurements were performed. From ventricular tissue, single myocyte shortening and relaxation were determined, and Ca2+transport was measured in homogenates and SR-enriched microsomes. Levels of mRNA and protein content were determined for the SR Ca2+-ATPase (SERCA2a), phospholamban (PLB), cardiac ryanodine receptor (RyR-2) and calsequestrin. The administration of DITPA improved LV contraction and relaxation and improved myocyte shortening in infarcted animals. The improvements in LV and myocyte function were associated with increases in Vmaxfor SR Ca2+transport in both homogenates and microsomes. Also, DITPA prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2 post-infarction, without measurable changes in mRNA levels. The thyroid hormone analogue, DITPA, improves LV, myocyte and SR function in infarcted hearts and prevents the downregulation of SR proteins associated with post-infarction heart failure. The specific effects of DITPA on post-infarction SR Ca2+transport and the expression of SR proteins make this compound a potentially useful therapeutic agent for LV systolic and/or diastolic dysfunction. |
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